Gamma-hydroxybutyric acid (GHB) is a therapeutic and a purported neurotransmitter (Nicholson et al, Drug Alcohol Depend., 63:1 (2001)). GHB is also known as 4-hydroxybutyrate and sodium oxybate. While there are many beneficial uses for GHB, GHB is also included in a class of drugs that have been abused, for example in cases of “date rape” and as an intoxicant.
GHB has a complex mechanism of action in vivo due to direct actions at GHB receptors and at GABAB receptors. In addition to being an agonist at GABAB receptors, GHB is rapidly metabolized to gamma-aminobutyric acid (GABA) (Bernasconi et al, Trends Pharmacol. Sci., 20:135 (1999)), resulting in GABAergic activity in vivo (Carai et al, Eur. J. Pharmacol., 428:315 (2001); and Cammalleri et al, Neuropsychopharmacology, 27:960 (2002)).
To allow for the separation of actions mediated through GHB receptors from those mediated through the GABA system, there is a need in the art to develop potent and selective GHB agonists, which do not have affinity for GABA receptors and which are not converted to GABA active compounds through metabolism.
Other researchers have prepared GHB NCEs, but all possess GABA activity or the potential to be metabolized to GABAergic agents. Wu et al have reported the developement of tertialy alcohol derivitives of GHB, which can not be metabolized to GABA-active compounds. Wu et al, J. Pharmacol. Exp. Ther., 675:305 (2003). However, there continues to be a need for high affinity metabolically-stable analogs of GHB that have little or no affinity for GABA receptors.